Most neurons in the adult CNS are terminally differentiated, and are thus not replaced after injury or disease related neuronal cell death. However, neural stem cells with multilineage potential are present in the adult CNS, and many factors including age and injury affect proliferation and differentiation of resident stem cells. Further, studies in young animals suggest that grafting of embryonic neural stem cells is useful for repairing the injured CNS. Nonetheless, it is unknown whether: (i) the responses of resident neural stem cells to injury change as a function of the age of the organism; and (ii) the stem cells grafted to the lesioned aging CNS are capable of integrating with the host tissue to produce both structural and functional recovery. Using a lesion model of the hippocampus, this project will elucidate how the post-injury responses of adult neural stem cells change during aging, and the efficacy of grafted embryonic neural stem cells for repair of the lesioned brain of different ages. There are three major hypotheses underlying the proposed experiments. (1) The number of resident stem cells that exhibit proliferation in response to a lesion in the hippocampus undergoes a significant decline as a function of the age of the organism (2) Sequential exogenous applications of a mitogen the fibroblast growth factor (FGF-2) and a differentiation factor the brain-derived neurotrophic factor (BDNF), enhance proliferation response of resident stem cells in the lesioned aging hippocampus. (3) Embryonic hippocampal CA3 region stem cells pre-treated and grafted with BDNF into the lesioned CA3 region of the hippocampus differentiate into CA3 pyramidal neurons and integrate into the host brain, independent of the age of the host at the time of the lesion. These hypotheses will be evaluated using the following measurements in young adult, middle-aged and aged Fischer 344 rats. (1) Stem cell proliferation and differentiation within the dentate gyrus of the hippocampus in both intact and lesioned conditions, and in the lesioned condition with sequential exogenous applications of FGF-2 and BDNF. (2) Analyses of the survival, differentiation, and integration of hippocampal CA3 region stem cells pre-treated and grafted with BDNF into the lesioned hippocampus. Understanding of age-related alterations in the post-lesion plasticity of resident stem cells, and the integration of grafted embryonic stem cells into the lesioned brain of different ages, is of significant relevance for developing treatment modalities for aged individuals with neurodegenerative diseases.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Project (R01)
Project #
5R01AG020924-03
Application #
6744766
Study Section
Special Emphasis Panel (ZAG1-FAS-9 (J2))
Program Officer
Wise, Bradley C
Project Start
2002-05-15
Project End
2007-04-30
Budget Start
2004-05-15
Budget End
2005-04-30
Support Year
3
Fiscal Year
2004
Total Cost
$292,600
Indirect Cost
Name
Duke University
Department
Surgery
Type
Schools of Medicine
DUNS #
044387793
City
Durham
State
NC
Country
United States
Zip Code
27705
Shetty, Geetha A; Hattiangady, Bharathi; Shetty, Ashok K (2013) Neural stem cell- and neurogenesis-related gene expression profiles in the young and aged dentate gyrus. Age (Dordr) 35:2165-76
Shetty, Ashok K; Hattiangady, Bharathi; Rao, Muddanna S et al. (2012) Neurogenesis response of middle-aged hippocampus to acute seizure activity. PLoS One 7:e43286
Shetty, Ashok K; Hattiangady, Bharathi; Rao, Muddanna S et al. (2011) Deafferentation enhances neurogenesis in the young and middle aged hippocampus but not in the aged hippocampus. Hippocampus 21:631-46
Shetty, Ashok K (2010) Issues to ponder when correlating hippocampal neurogenesis to a hippocampal-dependent memory function. Neurobiol Aging 31:2181-4
Kuruba, Ramkumar; Hattiangady, Bharathi; Shetty, Ashok K (2009) Hippocampal neurogenesis and neural stem cells in temporal lobe epilepsy. Epilepsy Behav 14 Suppl 1:65-73
Rao, Muddanna S; Hattiangady, Bharathi; Shetty, Ashok K (2008) Status epilepticus during old age is not associated with enhanced hippocampal neurogenesis. Hippocampus 18:931-44
Hattiangady, Bharathi; Shetty, Ashok K (2008) Aging does not alter the number or phenotype of putative stem/progenitor cells in the neurogenic region of the hippocampus. Neurobiol Aging 29:129-47
Acharya, Munjal M; Hattiangady, Bharathi; Shetty, Ashok K (2008) Progress in neuroprotective strategies for preventing epilepsy. Prog Neurobiol 84:363-404
Shetty, Ashok K; Rao, Muddanna S; Hattiangady, Bharathi (2008) Behavior of hippocampal stem/progenitor cells following grafting into the injured aged hippocampus. J Neurosci Res 86:3062-74
Hattiangady, Bharathi; Shetty, Ashok K (2008) Implications of decreased hippocampal neurogenesis in chronic temporal lobe epilepsy. Epilepsia 49 Suppl 5:26-41

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